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MOLECULAR MODELING EVALUATION OF A SERIES OF OXOQUINOLINE ANALOGS AS POTENCIAL HIV-1 REVERSE TRANSCRIPATASE INHIBITORS
1Assumpção RS, 1Souza TML, 1Frugulhetti ICPP, 2Faro LV, 2Santos FC, 2Silva DO, 2Cunha AC, 2Ferreira VF, 2Souza MCBV, 3Albuquerque MG, 4Rodrigues CR, 1Castro HC
1Deptº Biologia Celular e Molecular - UFF; 2Instituto de Química - UFF; 3Deptº Química Orgânica – UFRJ; 4Fac Farmácia - UFRJ.
The objective of this work is to evaluate the potential inhibitory activity of three oxoquinoline analogs on HIV-1 Reverse Transcriptase (RT) enzyme, using molecular modeling techniques, since these compounds have already been shown to inhibit HSV-1 in cell culture assays and they show structural analogy with a class of non-nucleoside RT inhibitors (NNRTIs).
Three-dimensional structures of compounds 1, 2, and 3 were assembled and manually docked into the NNRTI binding site of the RT structure guided by superposition using as a reference the crystal structure of HIV-1 RT in complex with GW426318 (PDB code 1TKT), a quinolinone derivative. Three alignments were tried for each compound according to their structural analogy with the GW426318 derivative.
The binding sites were isolated from the enzyme in pockets containing amino acids residues until 15Å of radius from the nitrogen atom of the oxoquinoline ring. The structures of the three complex models (ligand-RT) were energy minimized until to reach a gradient of 0.1 Kcal/mol. Finally, the complexation energy were calculated as the difference between the energy of the complex and the sum of the energies of the both isolated complex components. All calculations were carried out with the Hyperchem 7.0 program using the MM+ force field.
The results indicate that compound 1 shows the lowest complexation energy value using Alignment 1, corresponding to the most stable binding mode. Compound 2 shows complexation energy values higher than compound 1 using Alignments 1 and 2, however it shows a lower complexation energy values using Alignment 3. Finally, compound 3 shows the highest complexation energie values of all compounds considering all alignments, corresponding to the least stable binding modes.
The complexation energy values of three oxoquinoline derivatives docked at the NNRTI binding site of HIV-1 RT were calculated using molecular mechanics approach and the results are in agreement with preliminary pharmacological assays. Compound 1 has shown the best performance in this series, presenting the most stable binding mode considering three different trial alignments.
PIBIC-CNPq - CNPq - CAPES - FAPERJ - FUJB-UFRJ
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